Sir,

This was the case of a 53-year-old female patient who consulted due to dark spots on her face present for the previous five years. She used hydroquinone-based creams for four and a half years, noticing that the spots became darker, which led her to seek medical advice. She has no relevant family or personal medical history.

On dermatological examination, localized dermatosis on the face was observed, affecting both cheeks and peri- and infraorbital regions, with predominance on the right side, it consisted of dark spots and micropapules in some areas, along with hypochromic spots (Figs. 1a and 1b). The rest of the physical examination was within normal limits. Based on these findings, a diagnosis of exogenous ochronosis was made, and a skin biopsy was taken.

Figure 1: (a and b) Dark spots and micropapules in the malar and periorbital areas.

The skin biopsy showed an epidermis without architectural alterations, and in the reticular dermis, there were coffee-yellow deposits in the shape of rods or bananas, associated with focal elastosis (Fig. 2a); coffee-yellow deposits and collagen fibers with basophilic degeneration were also observed (Fig. 2b). At 40x magnification, coffee-yellow deposits in the shape of bananas were seen. The arrowhead points to the basophilic degeneration of the collagen fibers (Fig. 2c). Based on these findings, the clinical diagnosis of exogenous ochronosis was confirmed. After the diagnosis, the patient did not return for follow-up.

Figure 2: (a) Epidermis without abnormalities. Coffee-yellow deposits in the shape of rods or bananas in the reticular dermis associated with focal elastosis. (b) Coffee-yellow deposits and collagen fibers with basophilic degeneration. (c) Coffee-yellow deposits in the shape of bananas (40x magnification).

Ochronosis is a skin condition caused by the accumulation of phenols, either from within the body, such as homogentisic acid in people with alkaptonuria, or from external sources such as hydroquinone-containing topical creams [1].

Endogenous ochronosis, linked to alkaptonuria, causes a buildup of homogentisic acid in the urine, leading to darkening when exposed to air. It also results in bluish-black pigmentation in collagen-rich tissues, affecting the eyes, skin, heart, and urinary system. Exogenous ochronosis, caused by prolonged use of hydroquinone-based skin lighteners, leads to localized hyperpigmentation, usually on the face, without systemic symptoms. It primarily affects individuals with darker skin tones, such as Black South Africans and Hispanics, who use hydroquinone products for extended periods of time [1,2].

Hydroquinone (benzene-1,4-diol) is a phenolic compound with melanin-inhibiting and antioxidant properties. It has been used in skin-lightening creams to treat conditions such as melasma, post-inflammatory hyperpigmentation, and other skin disorders. It reduces pigmentation by affecting melanocytes, disrupting melanosome formation, and eventually causing their degradation [3].

The risk of exogenous ochronosis rises with hydroquinone concentrations over 2%, especially in alcoholic formulations. Although hydroquinone and similar products are used for various skin issues, treating exogenous ochronosis is challenging because the hyperpigmentation it causes counteracts the desired effect. This often leads users to apply higher concentrations or use the products more often, worsening the condition [4].

Exogenous ochronosis is considered rare yet may occur in all skin types. It typically appears symmetrically in sun-exposed areas, especially over the bony prominences. Clinically, exogenous ochronosis manifests as bluish-gray macules or papules on the photo-exposed areas of the face and neck [5,6].

Exogenous ochronosis may be classified into three stages, as outlined by Dogliotti and Leibowitz. Stage I involves erythema and mild hyperpigmentation, stage II involves hyperpigmentation, black colloid milia (caviar-like lesions), and atrophy, and stage III is characterized by papulo-nodular lesions. This classification aids in monitoring disease progression and treatment outcomes. While most affected patients have Fitzpatrick skin types III to VI, exogenous ochronosis should still be considered in those with skin types I–II if the clinical signs are present [4].

In exogenous ochronosis, dermoscopy reveals dense, brownish-black and blue-gray structures, which are further classified as globular, annular, or arciform in shape, and sometimes described as curvilinear or worm-like. These structures correspond to banana-shaped ochre deposits found in the upper dermis on histopathological examination. Additionally, dermoscopy may show obliterated follicular openings, scattered structureless areas, and telangiectasias [5].

The gold standard for diagnosing exogenous ochronosis is taking a biopsy, which reveals ochronotic fibers under microscopy. A biopsy is crucial as exogenous ochronosis may occur alongside other dyschromic disorders, ensuring a definitive diagnosis. However, dermoscopy, an often underutilized tool, may assist in diagnosis and may reduce the need for a biopsy. Dermoscopy findings, such as the obliteration of follicular openings, correlate with biopsy-confirmed histological features of exogenous ochronosis. If dermoscopy and the patient’s history are consistent with exogenous ochronosis, a biopsy, especially in sensitive facial areas, may be avoided. Nevertheless, since exogenous ochronosis and melasma may co-exist, a thorough evaluation of all dyschromic areas is necessary to exclude both conditions [4].

Endogenous and exogenous ochronosis have identical histological features, including curvilinear yellowish-green elastic fibers and banana-shaped amorphous material in the affected dermis. The epidermis is usually normal, although pseudoepitheliomatous hyperplasia may occur. In chronic cases, ochronotic fibers may break down into colloid milium, with notable inflammatory changes such as multinucleated giant cells, epithelioid histiocytes, and plasma cells. Diagnostic tools such as dermoscopy, reflectance confocal microscopy, and UV surface excitation microscopy may assist in diagnosing ochronosis [1,6].

This paradoxical hyperpigmentation, which is believed to result from the use of skin-lightening agents, is highly distressing for many patients and may often be confused with other types of dyschromia, including melasma, post-inflammatory hyperpigmentation, and Riehl’s melanosis [4].

Exogenous ochronosis is difficult to treat and may not be reversible. Treatment options for exogenous ochronosis have yielded suboptimal results, with cryotherapy, tretinoin, and topical acetic acid showing limited success. However, promising outcomes have been reported with Q-switched alexandrite and ruby lasers, CO₂ laser, and dermabrasion. Despite these treatments, it remains challenging to manage, highlighting the importance of early detection [1,7].

For treatment, discontinuing the causative agent is recommended, yet improvement may take years. Lasers offer the most promising therapy, although results may still be unsatisfactory. The CO₂ laser was the first reported modality, followed by quality-switched (QS) lasers, such as ruby (694 nm), alexandrite (755 nm), and Nd: YAG (1,064 nm), which have shown better results. More recently, improvement has been noted with intense pulsed light (IPL) using a 570 nm filter, Nd: YAG picosecond lasers (1064 nm), and laser combinations such as QS Nd: YAG followed by CO₂ [6].

When dermatologists prescribe hydroquinone for skin lightening, pigmentation, or melasma, patients often use the cream more frequently than recommended, hoping for faster improvement. However, they may not be aware of the potential serious side effects, such as exogenous ochronosis, leading to distress and depression. Therefore, hydroquinone prescriptions should be given with clear guidance on its potential risks, and the patient should be counseled to use it for as little time as necessary.

In conclusion, proper education and caution are essential when prescribing hydroquinone to prevent adverse effects and ensure the patient’s well-being.

REFERENCES

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2.Sunkara HP, Kilaru KR, Kumar AP, Ramineni HB, Krishna PR. A case report on hydroquinone induced exogenous ochronosis. Int J Adv Med. 2020;7:337-9.

3.Jimbow K, Obata H, Pathak MA, Fitzpatrick TB. Mechanism of depigmentation by hydroquinone. J Invest Dermatol. 1974;62:436-49.

4.Lazar M, De La Garza H, Vashi NA. Exogenous ochronosis:Characterizing a rare disorder in skin of color. J Clin Med. 2023;12:4341.

5.Khunger N, Kandhari R. Dermoscopic criteria for differentiating exogenous ochronosis from melasma. Indian J Dermatol Venereol Leprol. 2013;79:819.

6.Ceglio WW, Careta MF, Patriota R, Torezan LA. Exogenous ochronosis successfully treated with the combination of intense pulsed light and fractional CO₂ laser. An Bras Dermatol 2023;98:138-40.

7.Patel N, Shah H. Exogenous ochronosis from skin-lightening cream. N Engl J Med. 2024;390:254.